Synthesis of bile acids

The primary action of BARs is to bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids, which decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the... 

Drugs (B). Colestyramine and colestipol are nonabsorbable anion-exchange resins. By virtue of binding bile acids, they promote consumption of cholesterol for the synthesis of bile acids the 2000 Thieme... 

Cholesterol can be derived from two sources—food or endogenous synthesis from ace-tyl-CoA. A substantial percentage of endogenous cholesterol synthesis takes place in the liver. Some cholesterol is required for the synthesis of bile acids (see p. 314). In addition, it serves as a building block for cell membranes (see p. 216), or can be esterified with fatty acids and stored in lipid droplets. The rest is released together into the blood in the form of lipoprotein complexes (VLDLs) and supplies other tissues. The liver also contributes to the cholesterol metabolism by taking up from the blood and breaking down lipoproteins that contain cholesterol and cholesterol esters (HDLs, IDLs, LDLs see p.278). 

A number of cytochrome P450 enzymes are involved in the conversion of acetate to sterols and bile acids (Figure 9.6). The participation of P450 enzymes in pathways of cholesterol biosynthesis and elimination demonstrate their important role in cholesterol homeostasis. Lanosterol 14a-desmethylase, encoded by CYP51A1, is a pivotal P450 involved in cholesterol biosynthesis. The synthesis of bile acids from... 

The second step in the synthesis of bile acids, according to Hylemon et al. (1991), is the conversion of 7a-hydroxycholesterol to 7a-hydroxy-4-cholesten-3-one by NAD+-dependent 3/3-hydroxy-A5-C27-steroid oxidoreductase. This enzyme is located in the endoplasmic reticulum of liver, and its catalysis of the 3/3-hydroxy group also results in isomerization of the double bond from A5 to A4. 

Maintenance of cholesterol homeostasis. As outlined above, the cholesterol required is either obtained from the diet in the form of chylomicron remnants or is synthesised de novo. The synthesis of bile acids from cholesterol and their subsequent excretion in the faeces represent the only significant mechanism for the elimination of excess cholesterol. 

Bile acid production amounts to 400-500 mg/day (ca. 1 mmol). Excretion in the stool is of a similar order accordingly, renewed synthesis of bile acids is determined by the daily loss. Excretion in the urine lies below 0.5 mg/day (8 gmol/day) - this small amount may be disregarded. 

In summary, these studies demonstrated that in CTX the impaired synthesis of bile acids is due to a defect in the biosynthetic pathway involving the oxidation of the cholesterol side-chain. As a consequence of the inefficient side-chain oxidation, increased 23, 24 and 25-hydroxylation of bile acid precursors occurs with the consequent marked increase in bile alcohol glucuronides secretions in bile, urine, plasma and feces (free bile alcohols). These compounds were isolated, synthesized and fully characterized by various spectroscopic methods. In addition, their absolute stereochemistiy determined by Lanthanide-Induced Circular Dichroism (CD) and Sharpless Asymmetric Dihydroxylation studies. Further studies demonstrated that (CTX) patients transform cholesterol into bile acids predominantly via the 25-hydroxylation pathway. This pathway involves the 25-hydroxylation of 5P-cholestane-3a,7a, 12a-triol to give 5P-cholestane-5P-cholestane-3a,7a,12a,25- tetrol followed by stereospecific 24S-hydroxylation to yield 5P-cholestane-3a,7a,12a,24S,25-pentol which in turn was converted to cholic acid. 

The bile acid pool normally consists of about 2-4 g of conjugated and unconjugated primary and secondary bile acids. Daily loss of bile acids in feces, mostly as lithocholate, is about 0.2-0.4 g. Hepatic synthesis of bile acids equals this amount, so that the size of the bile acid pool is maintained at a constant level. 

Answer D. Cholestyramine and colestipol are resins that sequester bile acids in the gut, preventing their reabsorption. This leads to release of their feedback inhibition of 7-alpha hydroxylase and the diversion of cholesterol toward new synthesis of bile acids. Increase in high-affinity LDL receptors on hepatocyte membranes decreases plasma LDL. These drugs have a small but significant effect to increase plasma HDL rather than decrease it, but their ability to increase TGs precludes their clinical use in the management of hypertriglyceridemias. 

This rare inherited hpid storage disease is characterized by xanthomas, progressive neurological dysfunction, cataracts and the development of xanthomatous lesions in the brain and lung. In contrast to other diseases with tendon xanthomatosis, plasma cholesterol levels are remarkably low. Large deposits of cholesterol and cholestanol are present in most tissues, and the concentration of cholestanol is 10-100 times higher than normal. Salen and collaborators have made extensive and elegant studies on the various metabolic aspects of this disease [184,185,187-192]. They have conclusively shown that there is a subnormal synthesis of bile acids and that the metabolic defect is an impaired oxidation of the cholesterol side chain. The synthesis of chenodeoxycholic acid is reduced more than that of cholic acid. These patients excrete considerable amounts of bile alcohol in bile and faeces. The bile alcohols have been identified as 5)S-cholestane-3a,7a,12a,25-tetrol, 5 8-cholestane-3a,7a,12a,24,25-pentol and 5/8-cholestane-3 ,7a,12a,23,25-pentol. Two different explanations for the accumulation of these bile alcohols have been presented. 

In an early work by Myant and Eder, a time lag was observed between the increase in synthesis of cholesterol and synthesis of bile acids [221]. Such a time lag has not been reported in later studies, and it seems likely that the two rate-limiting enzymes respond to the same signal. The possibility that an increase of available cholesterol is responsible for the increase of cholesterol 7a-hydroxylation seems excluded by the work by Mitropoulos et al. in which attempts were made to measure the substrate of the enzyme under different condition [59,222]. In view of the time lag between introduction of a bile fistula and rise of enzyme activities, it is likely that protein synthesis is involved in the increase of both enzyme activities. 

Another nuclear receptor, called FXR, is activated by the binding of bile acids. Expressed in hepatocytes and intestinal epithelial cells, FXR plays a key role in regulating the en-terohepatlc circulation of bile acids. Bile acid-activated FXR stimulates the expression of Intracellular bile acid-binding protein (I-BABP) and of transport proteins (e.g., ABCBll, NTCP) that mediate cellular export and Import of bile acids (see Figure 18-11). In contrast, active FXR represses the expression of cholesterol 7a-hydroxylase, thereby decreasing the synthesis of bile acids from cholesterol in the liver—another example of end-product Inhibition of a metabolic pathway. Both FXR and LXR function as heterodimers with the nuclear receptor RXR. 

The interruption of enterohepatic recirculation of bile acids by the resins effectively lowers plasma cholesterol levels since cholesterol must now be diverted to de novo synthesis of bile acids. In addition, intestinal absorption of dietary cholesterol, normally facilitated by bile acids, is also reduced due to their excretion. Two significant compensatory mechanisms are called into action increased activity of hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase), which is the rate-controlling enzyme in the hepatic synthesis of cholesterol (see Fig. 11-4 and discussion to follow), and an increase in the number of LDL receptors. The latter mechanism offered the first meaningful treatment of heterozygous FH. Homozygous FH patients lacking LDL receptors, of course, do not respond. 

The existence of an alternate pathway for the synthesis of bile acids was suspected because it was possible for oxysterols to be converted into bile acids (N. Wachtel, 1968). It is now recognized that a variety of oxysterols produced by an assortment of cell types can be converted into bile acids. The production of these oxysterols is catalyzed by several sterol hydroxylases sterol 27-hydroxylase (CYP27A1) (J.J. Cali, 1991), cholesterol 25-hydroxylase (CH25H) (E.G. Lund, 1998), and cholesterol 24-hydroxylase (CYP46A1) (E.G. Lund, 1999). Cholesterol 25-hydroxylase is not a cytochrome P-450 monooxygenase, unlike the two other enzymes. Almost all of the 24-hydroxycholesterol that ends up in the liver originates from the brain, and it has been suggested that the production of... 

CYPs that catalyze steroid and bile acid synthesis have very specihc snbstrate preferences. For example, the CYP that prodnces estrogen from testosterone, CYP19 or aro-matase, can metabolize only testosterone, and does not metabolize xenobiotics. Specihc inhibitors for aromatase, snch as anastrozole, have been developed for use in the treatment of estrogen-dependent tnmors. The synthesis of bile acids from cholesterol occnrs in the liver where, snbseqnent to CYP-catalyzed oxidation, the bile acids are conjngated and transported throngh the bile duct and gallbladder into the small intestine. CYPs involved in bile acid prodnction have strict snbstrate reqnirements and do not participate in xenobiotic or drng metabolism. 

Synthesis of bile acids and salts from cholesterol is shown in Figure 19.23. These reactions involve enzymes called microsomal P450 mixed-function oxidases. The first reaction, in which cholesterol is converted to 7-ot-hydroxycholesterol, is the rate limiting step. 

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